In the early stages of drug development, an important focus for researchers is the risk of drug-induced cardiovascular effects. More commonly known as an abnormal heart rhythm, arrhythmia is a term used to describe when the heart is beating too quickly, too slowly or irregularly. The consequences of arrhythmia can be fatal. Read More
In preclinical pharmacology studies designed to establish the safety profile of a new drug as part of the development process, the effects on subject’s electrocardiogram (ECG) are closely examined. The QT interval is a measure of the electrical properties of the heart and prolongation of this interval indicates a disturbance in electrical conduction of the heart’s bottom chambers (ventricles). Various chemical compounds can interfere with a specific ion channel encoded by the human Ether-à-go-go-Related Gene or hERG, which is located on these cells and is responsible for the electrical changes observed on the ECG. In fact, several drugs have been withdrawn from the U.S. market or have received label warnings due to their potential to cause QT interval prolongation that leads to fatal arrhythmias and sudden cardiac death.
As such, QT interval prolongation is used as an important biomarker for drug-induced arrhythmia risk in cardiovascular safety studies and is listed in the guidelines of the International Council on Harmonization and other regulatory agencies.
Unfortunately, the QT interval is highly variable, and researchers must correct for this variation between research subjects in their measurements. The main correction approaches are to control statistically for the effects of heart rate. As the term suggests, universal QT-correction methods apply a fixed formula to do this, and do not consider how the relationship between QT interval and heart rate differs not just between subjects but even for the same subject at different points in time. Furthermore, circadian rhythms and other external factors also influence the QT and heart rate relationship. These observations call into serious question whether universal QT-correction methods are viable or appropriate.
Dr Adam Lauver at Michigan State University and collaborators in the pharmaceutical industry are working on the development of improved correction methods that are specific to each individual. Here, the correction is based on the subject-specific relationship between QT and heart rate, rather than a universal correction.
In a recent study, Dr Lauver and colleagues used data from eight animal toxicology studies provided by pharmaceutical industry partners to compare universal and individual correction methods. The researchers confirmed that more effective and consistent correction was obtained when using the subject-specific approach. Thus, better understanding the individual relationship between QT and heart rate reduces the variability typically observed, thereby improving the sensitivity of QT prolongation detection while using fewer subjects.
In a subsequent study, Dr Lauver and colleagues expanded on their prior findings using existing data from studies evaluating drugs that are known to cause QT prolongation. They reported a novel subject-specific correction formula, called QT Ratio, and compared this new method with several other methods of QT correction. The investigators concluded that the QT Ratio method consistently provided improved correction of the heart rate effect on QT and increased sensitivity of detecting the effects of drugs compared to traditional correction methods.
The Ratio method offers a promising alternative for use in nonclinical drug safety studies investigating cardiovascular effects. Critically, gaining a more accurate understanding of the dose-dependent effect a drug has on the QT interval will ensure more reliable outcomes in preclinical drug safety studies.
